Huntington's disease (HD) MedDRA version: 20.0 Level: PT Classification code 10070668 Term: Huntington's disease System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Sponsors
F.Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Age 25-50 years - Huntington’s disease (HD) gene expansion mutation carrier status - Either: - Prodromal HD or Early manifest HD - Estimated glomerular filtration rate >= 60 mL/min/1.73 m2 in at least one out of two maximum screening samples - Total body weight > 40 kg and a body mass index within the range of 18-32 kg/m2 - Ability to read the words "red," "blue," and "green" and be fluent in the language of the Informed Consent and the tests used at the study site - Ability to walk unassisted without a cane or walker and move about without a wheelchair on a daily basis as determined at screening and baseline visit (Day 1) - Ability to undergo and tolerate MRI scans - Ability to tolerate blood draws and lumbar punctures (LPs) - Stable medical, psychiatric, and neurologic status as assessed by physician for at least 12 weeks prior to screening and at the time of enrollment - Negative hepatitis B surface antigen test at screening - Negative hepatitis C virus (HCV) antibody test at screening, or a positive HCV antibody test followed by a negative HCV ribonucleic acid (RNA) test at screening - For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agree to refrain from donating eggs during the treatment period and for 5 months after the final dose of the study drug. Female participants must refrain from donating eggs during this same period - For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom and agree to refrain from donating sperm during the treatment period and for 5 months after the final dose of the study drug to avoid exposing the embryo. Male participants must refrain from donating sperm during this same period Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 300 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - History of attempted suicide or suicidal ideation with plan that required hospital visit and/or change in level of care within 12 months prior to screening - Active psychosis, confusional state, or violent behavior, including aggression that could cause harm to self or others, over the 12 weeks prior to screening - Clinical diagnosis of chronic migraines as per the International Headache Society Classification of Headache Disorders - Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of study drug - Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter - Hydrocephalus - History of deep brain stimulation - Known human immunodeficiency viruses (HIV) infection - An infection requiring oral or intravenous antibiotics within 14 days prior to screening, during screening and prior to randomization - Anti-retroviral medications, including anti-retroviral medication taken as prophylaxis within 12 months of study enrollment - Current or previous use of an antisense oligonucleotide (ASO) or any huntingtin protein (HTT) lowering therapy - Treatment with investigational therapy within 4 weeks or 5 drug-elimination half-lives, whichever is longer, prior to screening - Current or previous history of a primary independent psychotic disorder - Current use of anti-psychotics for motor symptoms or mood stabilization and/or tetrabenazine, valbenazine, or deutetrabenazine at a dose that has not been stable for at least 12 weeks prior to screening or is anticipated to change during the study, including at screening - Cholinesterase inhibitors, memantine, or riluzole use within 12 weeks from initiation of study treatment - Current use of amantadine, anti-depressant or benzodiazepine at a dose that has not been stable for at least 12 weeks prior to screening or is anticipated to change during the study, including at screening - Current use of supplements used to treat HD symptoms, including in an experimental setting, at a dose that has not been stable for at least 6 weeks prior to screening or is anticipated to change during the study, including at screening - Anti-platelet or anticoagulant therapy within 14 days prior to screening - History of bleeding diathesis or coagulopathy - Platelet count less than the lower limit of normal - History of gene therapy, cell transplantation, or brain surgery - Planned brain surgery during the study - Concurrent or planned participation in any interventional clinical study, including explicit pharmacological and non-pharmacological interventions. Observational studies are acceptable; however, data collection is not permitted between screening and baseline visits and throughout the duration of the study - Poor peripheral venous access - Scoliosis or spinal deformity or surgery making intrathecal (IT) injection not feasible in an outpatient setting and potentially interfering with distribution of tominersen up the neuraxis - Malignancy within 5 years prior to screening, except basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated - Preexisting intra-axial or extra-axial lesions as assessed by a centrally read MRI scan during the screening period
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - To evaluate the safety of tominersen compared with placebo on the basis of incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale, change from baseline in clinical laboratory results [cerebrospinal fluid (CSF) white blood cell (WBC) and protein], and safety magnetic resonance imaging (MRI) - To evaluate CSF mutant huntingtin (mHTT) protein levels in response to tominersen compared with placebo at 9 months - To evaluate the efficacy of tominersen compared with placebo on the basis of change from baseline in composite unified huntington's disease rating scale (cUHDRS) (non-U.S.) and total functional capacity (TFC) (U.S.) at 16 months ;Secondary Objective: - To evaluate the safety of tominersen compared with placebo on the basis of change from baseline in vital signs, electrocardiogram (ECG) parameters, plasma clinical laboratory results, montreal cognitive assessment (MoCA), and proportion of participants with suicidal ideation or behavior as assessed by columbia-suicide severity rating scale (C-SSRS) score at each visit -To evaluate the efficacy of tominersen compared with placebo on the basis of change from baseline at 16 months for the assessments of TFC (non-U.S.)/cUHDRS (U.S.), symbol digit modalities test (SDMT) stroop word reading (SWR) and total motor score (TMS) - To evaluate change from baseline in CSF neurofilament light chain (NfL) in response to tominersen compared with placebo at 16 months - To evaluate the immune response to tominersen ;Primary end point(s): 1. Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale 2. Change from baseline in clinical laboratory results (CSF WBC and protein) 3. Safety MRI 4. Percentage change from baseline in geometric means of CSF mHTT protein levels at Month 9 5. Change from baseline in cUHDRS (non-U.S.) and TFC (U.S.) at 16 months ;Timepoint(s) of evaluation of | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Change from baseline in vital signs 2. Change from baseline in ECG parameters 3. Change from baseline in plasma clinical laboratory results 4. Change from baseline in MoCA 5. Proportion of participants with suicidal ideation or behavior as assessed by C-SSRS score at each visit, including detailed focus on any individual cases identified as having severe ideation or behavior during the study conduct 6. Change from baseline at 16 months for the assessments of TFC (non-U.S.)/cUHDRS (U.S.), SDMT, TMS, and SWR 7. Change from baseline in CSF NfL levels at 16 months 8. Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence of ADAs at baseline 9. Titers will be determined if ADAs are identified ;Timepoint(s) of evaluation of this end point: 1-3. Baseline visit (Day 1), and Months 4, 8, 9, 12, 16, ETT and SFU 4. Baseline and Months 4, 8, 9, 12, 16, ETT and SFU 5. Up to approximately 24 months 6-7. Baseline to 16 Months 8-9. Baseline, and Months 4, 8, 12, 16, ETT and SFU, subsequent clinic visit every 16 weeks, ETT and SFU | — |
Countries
Argentina, Australia, Austria, Canada, Denmark, Germany, New Zealand, Poland, Portugal, Spain, Switzerland, United Kingdom, United States
Contacts
Public ContactTrial Information Support Line-TISL
F.Hoffmann-La Roche Ltd
Outcome results
None listed